Purpose Roux en Y gastric bypass surgery (RYGB) is an effective therapy for patients with severe obesity. It induces both significant weight loss and rapid improvements of metabolic complications. This study was undertaken to better define the direct role of weight loss in the metabolic improvements. Methods A retrospective, case-control study of a cohort of 649 patients with obesity who underwent RYGB, comparing higher and lower responders at 2 years after surgery (n = 100 pairs). Pairs of patients were matched for age, gender, and initial BMI. The rates of remission of diabetes, hypertension, dyslipidemia, and hyperuricemia were compared using a mixed effects logistic regression analysis. Results Diabetes before surgery was present in 12/100 lower responders and 17/100 higher responders. Remission at 2 years was observed in 4/12 (33%) of lower responders, compared to 15/17 (88%) of higher responders. Thus, the odds of diabetes remission was significantly smaller in lower responders (OR = 0.067, 95% CI 0.01-0.447). A mixed model regression analysis of all the parameters for each patient showed that the odds of achieving remission of any comorbidity was significantly lower in lower responders (OR = 0.62, 95% CI = 0.39-0.97). Conclusion We could demonstrate that weight loss is a significant determinant of the remission of diabetes 2 years after RYGB. These data underline the importance of weight loss in the benefits of this procedure.